Patients with head and neck squamous cell carcinoma (HNSCC) are treated aggressively with surgery followed by radiation, often together with cisplatin (1). Although these treatments increase loco-regional control, they are frequently disfiguring and induce high-grade toxicities limiting their effectiveness (2). Furthermore, resistance to cisplatin and radiation contributes to tumor recurrence, and options for those who do not respond are limited to palliative care. Targeted therapies for HNSCC are scarce, limited to experimental agents targeting the epidermal growth factor receptor (3).
Mutations in the tumor suppressor gene p53 are very common in HNSCC, with an estimated frequency of >50% (4, 5). Disruptive p53 mutations have been associated with metastasis, resistance to radiation, and poor patient survival (6-8). Despite the strong implication of p53 in the biology and clinical outcome of HNSCC, there are no available therapies that specifically target p53 mutant cancer cells.
The present invention addresses this shortcoming by providing new therapies for the treatment of p53 mutant cancer cells, including HNSCC, as well as new methods for identifying therapeutic targets in cancers and other diseases.